Growing medico-legal and socio-cultural tolerance of marijuana use is fueling a rise in marijuana availability/use despite scientific evidence that regular marijuana use carries health risks. Cannabis use disorder (CUD) is the most commonly treated substance abuse problem, and escalating marijuana availability/use is likely to increase demand for treatment. There is no approved medication to treat CUD, and relapse rates after behavioral treatment are high. Despite an urgent need for pharmacological and psychosocial interventions, optimal treatments should be predicated on clear understanding of mechanisms that underlie marijuana use. Although it is clinically accepted that exposure to drug-related cues foreshadows drug taking, a causal link between cue-exposure and drug use has yet to be demonstrated under experimentally controlled conditions. Similarly, the extent to which craving mediates this link has not been examined. The proposed study aims to establish a human laboratory model to examine the effect of cue exposure on drug seeking (using marijuana as an exemplar) and the contribution of craving in the cue/seeking connection. Cue-induced seeking will be examined in the context of varying unit price (using a progressive ratio schedule) to obtain marijuana, to introduce variability in drug motivation and different environmental conditions. This hybrid cue-exposure + choice procedure model will be used to test whether N-acetylcysteine (NAC), a cysteine pro-drug, attenuates marijuana cue-related craving and seeking. In this placebo-controlled, within subject, randomized crossover, inpatient study, a total of 32 individuals with CUD will be administered NAC (0 vs 2400 mg) prior to marijuana and neutral cue exposure. Our primary outcome measure is marijuana-seeking behavior assessed using a marijuana (vs. money) choice, PR task. In each session, participants will be given 11 choice opportunities to work for puffs from a marijuana cigarette (7.0% THC; max of 11 puffs) or money alternative (max of $22). Aims are to determine whether: (1) presentation of polysensory marijuana-related vs. neutral cues increases marijuana seeking; (2) the Glu probe NAC attenuates the effects of marijuana-related cues on craving and seeking; and, (3) marijuana cue-induced craving mediates effects of cue exposure on drug seeking. Overall, this project will increase mechanistic understanding of cue-induced cannabis use and provide a model for screening therapeutic approaches to reduce health burdens of CUD. This project addresses a significant public health problem with an innovative and strong approach, and will have a substantial and sustained impact on the field.